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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 04 Aug 2020 at 01:33 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: alzheimer[TIAB] AND treatment[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2020-08-03

Naing HL, SP Teo (2020)

Impact of Hypertension on Cognitive Decline and Dementia.

Annals of geriatric medicine and research, 24(1):15-19.

Dementia reduces a person's ability to perform their activities of daily living and is the leading cause of morbidity worldwide. While most preventive measures are ineffective in reducing dementia risk, active treatment of hypertension in middle-aged and older adults without dementia may reduce the incidence of dementia. Hypertension is associated with vascular dementia but may also affect the manifestations of Alzheimer disease. Observational studies support the association between hypertension and white matter lesions, hippocampal atrophy, and cognitive decline. Both increased and decreased blood pressure were related to the development of white matter lesions. Cohort studies showed that hypertension treatment and treatment duration were associated with lower cognitive decline. This review describes findings from randomized controlled studies on the effects of antihypertensives on cognitive decline. Only the Systolic Hypertension in Europe (Syst-Eur) trial using calcium-channel blockers demonstrated a significant reduction in dementia incidence. Further studies are required to evaluate the long-term benefits of antihypertensive treatment in dementia.

RevDate: 2020-08-03

Ahmed Z, Aziz S, Hanif M, et al (2020)

Phytochemical screening and enzymatic and antioxidant activities of Erythrina suberosa (Roxb) bark.

Journal of pharmacy & bioallied sciences, 12(2):192-200.

Background: This study aimed to evaluate the phytochemicals screening of Erythrina suberosa (Roxb) bark and to analyze the enzymatic activities of its various organic fractions.

Materials and Methods: Crude methanolic fraction of E. suberosa (Roxb) bark and its respective fractions were screened for the presence of different phytochemicals with different reagents. On the basis of increasing order of polarity, different organic solvents were used to obtain different fractions. Enzymatic studies were performed on crude methanolic extract of the plant. All the assays were performed under standard in vitro conditions.

Results: The phytochemical analysis shows the presence of alkaloids, phenols, triterpenoids, phytosterols, and flavonoids. Phenolic compounds and flavonoids are the major constituents of the plant. In anticholinesterase assay, the percent inhibition of standard drug (eserine) was 91.27 ± 1.17 and the half maximal inhibitory concentration (IC50) was 0.04 ± 0.0001. For α-glucosidase inhibition, the IC50 value for Dichloromethane fraction was 8.45 ± 0.13, for Methanol fraction it was 64.24 ± 0.15, and for aqueous fraction it was 42.62 ± 0.17 as compared with standard IC50 that is 37.42 (acarbose). Furthermore, results show that all fractions have potential against anti-urease enzyme, but DCM fraction of crude aqueous extract has significant IC50 value (45.26 ± 0.13) than other fractions.

Conclusion: Keeping in view all the results, it is evident that the plant can be used in future for formulating effective drugs against many ailments. Secondary metabolites and their derivatives possess different biological activities, for example, .g. flavonoids in cancer, asthma, and Alzheimer. Furthermore, the extracts of this plant can be used in their crude form, which is an addition to the complementary and alternative treatment strategies.

RevDate: 2020-08-03

Hasegawa T, Kosoku Y, Sano Y, et al (2020)

Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.

Journal of Alzheimer's disease : JAD pii:JAD200234 [Epub ahead of print].

BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD.

OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD.

METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases.

RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%.

CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

RevDate: 2020-08-01

Abdeljalil AB, de Mauléon A, Baziard M, et al (2020)

Antidepressant Use and Progression of Mild to Moderate Alzheimer's Disease: Results from the European ICTUS Cohort.

Journal of the American Medical Directors Association pii:S1525-8610(20)30539-9 [Epub ahead of print].

OBJECTIVES: Neuropsychiatric symptoms (NPS) are a core and troubling feature among patients with Alzheimer disease (AD). Because of growing safety warnings against antipsychotics, the use of antidepressants (ATD) in AD has increased extensively. We investigated the potential long-term associations between ATD exposure and functional and cognitive progression in patients with mild to moderate AD.

DESIGN: Two-year prospective multicenter cohort ICTUS (Impact of Cholinergic Treatment USe) study with biannual assessments.

SETTING: Twenty-nine memory clinics from 12 European countries.

PARTICIPANTS: Community-dwelling patients with mild to moderate AD.

METHODS: Global cognitive function was measured using the Mini Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Functional impairment was measured using the Activities of Daily Living (ADL). Assessments were performed biannually for 2 years. Antidepressant exposure was defined by an ATD prescription for a minimum period of 6 months. Linear mixed models were used to study the associations between ATD exposure and cognitive and functional progression.

RESULTS: Antidepressant exposure was not associated with cognitive decline [MMSE: β-coefficients of the linear mixed models (Coef) = 0.06, 95% confidence interval (CI) -0.65 to 0.76, P = .87; ADAS-Cog: Coef = -13.9, 95% CI -34.80 to 7.03, P = .19] or with functional decline (ADL: Coef = -0.05, 95% CI -0.21 to 0.09, P = .48) at 2-year follow-up. Antipsychotic exposure at baseline was associated with a greater functional decline in the ADL score (Coef = -0.39, 95% CI - 0.68 to 0.10, P < .01).

CONCLUSIONS AND IMPLICATIONS: Antidepressant exposure was not associated with a faster rate of cognitive or functional decline in patients with mild to moderate AD. Antidepressants might be appropriate alternatives to antipsychotics in the management of NPS in mild to moderate AD.

RevDate: 2020-07-31

Sugin LJS, Murugesan A, Bindu M, et al (2020)

Roflumilast: A potential drug for the treatment of cognitive impairment?.

Neuroscience letters pii:S0304-3940(20)30551-6 [Epub ahead of print].

Phosphodiesterase-4 regulates the intracellular level of cAMP. Roflumilast, a selective PDE-4 inhibitor was the first agent in this class to have reached the market for patients with chronic obstructive pulmonary disease worldwide. Numerous preclinical evidences indicate the role of PDE-4 inhibitors in reversal of ageing-related alterations induced in animal models by various pharmacological agents, overexpression of mutant forms of human amyloid precursor proteins and in aging, as well. Roflumilast was capable of decreasing PDE-4B and 4D subtypes with an increase in the expression of pCREB and BDNF in hippocampus of rats. The beneficial effects of roflumilast on cognition are believed to be mediated through the above-mentioned cellular effects. Recently, our group had shown that roflumilast has improved the short and long-term memory in rodents. Several lines of evidence indicate that targeting PDE-4 inhibition might offer novel approaches in the treatment of age-associated memory impairment and in Alzheimer's disease. Likewise, in a recent report, roflumilast improved the memory functions in humans after administration of 100 µg of the drug, without the typical side effects of PDE-4 inhibitors, which might offer a novel therapeutic option for the treatment of cognitive impairment and Alzheimer disease. In the current article, the author reviews the most recent evidences demonstrating the beneficial effects of roflumilast on learning and memory in animal models and humans.

RevDate: 2020-07-29

Sun Y, Wang Y, Chen ST, et al (2020)

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.

Theranostics, 10(18):8430-8445 pii:thnov10p8430.

A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

RevDate: 2020-07-29

Varano F, Catarzi D, Vigiani E, et al (2020)

Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists.

Pharmaceuticals (Basel, Switzerland), 13(8): pii:ph13080161.

The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.

RevDate: 2020-07-26

Lushchekina SV, P Masson (2020)

Slow-binding inhibitors of acetylcholinesterase of medical interest.

Neuropharmacology pii:S0028-3908(20)30304-X [Epub ahead of print].

Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning.

RevDate: 2020-07-27

Tanaka N, Okuda M, Nishigaki T, et al (2020)

Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.

PloS one, 15(7):e0235979 pii:PONE-D-20-06596.

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.

RevDate: 2020-07-24

Mascarenhas AMS, de Almeida RBM, de Araujo Neto MF, et al (2020)

Pharmacophore-based virtual screening and molecular docking to identify promising dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.

Journal of biomolecular structure & dynamics [Epub ahead of print].

The dual inhibition of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) plays an important role in Alzheimer's disease treatment. Thus, this study aims identify promising dual inhibitors against hAChE and hBuChE by in silico approaches (pharmacophore-based virtual screening and molecular docking). Ten 3 D pharmacophore models for dual inhibitors using default genetic parameters were built by GALAHAD™ available on SYBYL-X 2.0. Validation steps were carried out according to Energy (<100.0 kcal/mol), Pareto = 0, Area under the ROC Curve (>0.70), Boltzmann-Enhanced Discrimination of ROC curve (BEDROC >0.50) and structure-activity relationship (SAR) for known inhibitors. The best dual pharmacophore model based on internal/external statistical parameters and SAR data (one hydrogen bond acceptor, two hydrogen bond donors and four hydrophobic centers) was employed in virtual screening at Sigma-Aldrich® subset (n = 214,446) of ZINC database by UNITY module of SYBYL-X 2.0. According to superposition values (QFIT), the best ranked compounds were prioritized for molecular docking and partition coefficient analysis (clog p < 5.0). 37 top-ranked compounds (QFIT > 64.22) from pharmacophore model showed affinity in hAChE (-10.2 < Affinity energy < -6.3 kcal/mol) and hBuChE (-10.9 < Affinity energy < -2.3 kcal/mol) binding sites. Next, liposolubity prediction and commercially available showed that ZINC43198636, ZINC43198637 and ZINC00390718 can be potential dual inhibitors against hAChE and hBuChE. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-07-23

Joseph CR (2020)

Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease.

Biomedicines, 8(7): pii:biomedicines8070228.

With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood-brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

RevDate: 2020-07-17

Ghai R, Nagarajan K, Arora M, et al (2020)

Current Strategies and Novel Drug Approaches for Alzheimer Disease.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-108224 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a chronic devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc are being used to manage the symptoms of Alzheimer's disease.

OBJECTIVE: The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals.

MATERIALS & METHODS: Enormous literature survey was conducted and published articles of PUBMED, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease.

RESULTS & CONCLUSION: Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

RevDate: 2020-07-17

Sokolova SV, Sozarukova MM, Khannanova AN, et al (2020)

[Antioxidant status in patients with paranoid schizophrenia and Alzheimer disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 120(6):82-87.

OBJECTIVE: To study the antioxidant profile of blood plasma in patients with paranoid schizophrenia and Alzheimer disease (AD).

MATERIAL AND METHODS: Thirty-three patients with paranoid schizophrenia and 18 patients with AD were included in the study. Patients with schizophrenia were stratified into two subgroups by response to therapy. The indicators of the antioxidant profile were determined using methods based on chemiluminometry and spectrofluorimetry.

RESULTS: Systemic oxidative stress due to insufficiency of low molecular weight plasma antioxidants is not determined neither in AD nor in treatment resistant schizophrenia. At the same time, a «thiol» oxidative stress, which indirectly indicates a deficiency of the glutathione system, is present in both groups. In patients with paranoid schizophrenia responsive to treatment, systemic oxidative stress is more pronounced and «thiol» oxidative stress is less significant. Among the antipsychotics studied, haloperidol, zuclopenthixol, risperidone and ziprasidone do not exhibit antioxidant properties, but periciazine, clozapine and especially chlorpromazine exhibit strong antioxidant properties, but they unlikely affect the antioxidant potential of blood plasma.

CONCLUSIONS: The glutathione part of the antioxidant system is mostly affected, but systemic oxidative stress is not significant in patients with treatment resistant paranoid schizophrenia and AD. Oxidative disorders are more pronounced in treatment responsive paranoid schizophrenia.

RevDate: 2020-07-17

Jin N, Ziyatdinova S, Gureviciene I, et al (2020)

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.

Scientific reports, 10(1):11851 pii:10.1038/s41598-020-68845-y.

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

RevDate: 2020-07-15

Koch G, Motta C, Bonnì S, et al (2020)

Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 3(7):e2010372 pii:2768248.

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).

Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.

This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.

Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).

Main Outcomes and Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.

Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.

Conclusions and Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.

Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.

RevDate: 2020-07-15

Wang X, Li W, Marcus J, et al (2020)

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy.

The Journal of pharmacology and experimental therapeutics, 374(2):252-263.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

RevDate: 2020-07-13

Liao Z, Cheng L, Li X, et al (2020)

Meta-analysis of Ginkgo biloba Preparation for the Treatment of Alzheimer's Disease.

Clinical neuropharmacology, 43(4):93-99.

OBJECTIVE: The objective of this study was to investigate the efficacy and safety of Ginkgo biloba preparation for the treatment of Alzheimer disease (AD).

METHODS: Both English (PubMed, Embase, Cochrane Library databases, and the Cochrane Controlled Trials Register) and Chinese (WanFang, Chinese Biomedical, CNKI, and VIP databases) databases were systematically and independently searched by 2 authors from their inception until July 3, 2019. All relevant studies included AD patients who were treated with Ginkgo biloba. The efficacy and safety of the medicine were used as the main measurement index.

RESULTS: Seven studies (N = 939) were identified and analyzed. When compared with placebo, Ginkgo biloba showed exact validity in cognitive function and global clinical assessment (cognitive function section: risk ratio = 1.98, 95% confidence interval = 1.52-2.59, Z = 5.12, P < 0.001; according to Clinical Global Impression Change: odds ratio = 3.119, 95% confidence interval = 2.206-4.410, Z = 6.44, P < 0.001). Adverse events were mild.

CONCLUSIONS: Ginkgo biloba preparation has reliable efficacy of cognitive function and global clinical assessment and safety in the treatment of AD.

RevDate: 2020-07-13

Fantini J, Chahinian H, N Yahi (2020)

Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?.

Protein science : a publication of the Protein Society [Epub ahead of print].

After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β-amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca2+ permeable pores in the membranes of brain cells. By triggering an intracellular Ca2+ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca2+ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This "histidine trick" can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti-oligomer targets will provide innovative opportunities to find an efficient cure. A "full efficient" solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.

RevDate: 2020-07-11

Rajabi F, Gusbeth C, Frey W, et al (2020)

Nanosecond pulsed electrical fields enhance product recovery in plant cell fermentation.

Protoplasma pii:10.1007/s00709-020-01534-9 [Epub ahead of print].

The potential of pharmacologically active secondary plant metabolites is limited by the low yield from often rare plants, and the lack of economically feasible chemical synthesis of these complex compounds. Plant cell fermentation offers an alternative strategy to overcome these constraints. However, the efficiency of this approach is limited by intracellular sequestration of the products, such that continuous bioprocessing is not possible. As a precondition for such a, more attractive, continuous process, it is of great importance to stimulate the export of the product into the medium without impairing viability and, thus, the productivity of the cells. Using nicotine alkaloids of tobacco as a case study, an alternative strategy is explored, where nanosecond pulsed electric fields (nsPEFs) are applied for the efficient downstream recovery of the products. To maintain cell viability and allow for the further use of biomass, cells were exposed to strong (1-20 kV·cm-1), but very short (10-100 ns) electric pulses, which leads to a temporary permeabilisation of cell membranes. Using two transgenic cell lines, where two key genes involved in the metabolism of the anti-Alzheimer compound nornicotine were overexpressed, we could show that this nsPEF treatment improved the partitioning of some nicotine alkaloids to the culture medium without impairing viability, nor the synthesis of alkaloids. However, this release was only partial and did not work for nornicotine. Thus, nsPEFs produced a fractionation of alkaloids. We explain this electrofractionation by a working model considering the differential intracellular compartmentalization of nicotineic alkaloids.

RevDate: 2020-07-10

Kısa D, Korkmaz N, Taslimi P, et al (2020)

Bioactivity and molecular docking studies of some nickel complexes: New analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.

Bioorganic chemistry, 101:104066 pii:S0045-2068(20)31363-8 [Epub ahead of print].

The interaction of the coordination compounds with biological molecules resulted in the investigation of the drug potential of these molecules. In this study, enzyme inhibition of DSA (1-3) coordination compounds that were previously investigated for their anticancer and antibacterial properties was investigated. Also, DSA (1-3) had Ki values of 635.30 + 152.62, 184.01 + 90.05, and 163.03 ± 60.01 µM against human carbonic anhydrase I, 352.23 ± 143.09, 46.2 ± 15.47, and 54.117 ± 18.80 µM against AChE, 310.64 ± 97.35, 35.54 ± 7.01, and 101.51 ± 15.314 µM against BChE, respectively. The biological activity values of these compounds against enzymes whose name are AChE, BChE, and hCAI were compared. Ellman and Verporte methods were used for the study of these enzymes. Cholinesterase inhibitors, also known as anti-cholinesterase and cholinesterase blocking drugs, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. They may be used as drugs for Alzheimer's and myasthenia gravis. It is a common method for comparing biological activity values of nickel complexes with molecular docking calculations. Nickel complexes were studied against enzymes that are human carbonic anhydrase isozyme I for ID 2CAB (hCA I), butyrylcholinesterase for ID 1P0I (BChE), and acetylcholinesterase for ID 1EEA (AChE), respectively.

RevDate: 2020-07-10

Liu B, Cao Y, Shi F, et al (2020)

The overexpression of RBM3 alleviates TBI-induced behaviour impairment and AD-like tauopathy in mice.

Journal of cellular and molecular medicine [Epub ahead of print].

The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.

RevDate: 2020-07-09

Kumar R, Gulati M, Singh SK, et al (2020)

Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-107983 [Epub ahead of print].

Vulnerability of the brain milieu to even the subtle changes in its normal physiology is guarded by a highly efficient blood brain barrier. A number of factors i.e. molecular weight of the drug, its route of administration, lipophilic character etc. play a significant role in its sojourn through the blood brain barrier (BBB) and limit the movement of drug into brain tissue through BBB. To overcome these problems, alternative routes of drug administration have been explored to target the drugs to brain tissue. Nasal route has been widely reported for the administration of drugs for treatment of Alzheimer. In this innovative approach, the challenge of BBB is bypassed. Through this route, both the larger as well as polar molecules can be made to reach the brain tissues. Generally, these systems are either pH dependent or temperature dependent. Results: The present review highlights the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of nasal drug delivery system, nasal formulations of various drugs that have been tried for their nasal delivery for treatment of Alzheimer. Conclusion: It also dives deep to understand the factors that contribute to the success of such formulations to carve out a direction for this niche area to be explored further.

RevDate: 2020-07-09

Azib L, Debbache-Benaida N, Da Costa G, et al (2020)

Neuroprotective effects of Fraxinus angustifolia Vahl. bark extract against Alzheimer's disease.

Journal of chemical neuroanatomy pii:S0891-0618(20)30117-4 [Epub ahead of print].

Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β aggregation and accumulation of neurotoxic metals in the brain. Fraxinus angustifolia Vahl. (Oleaceae) is a Mediterranean plant traditionally used to treat several human problems as nervous system problems. This study aimed to evaluate the neuroprotective effects of F. angustifolia Vahl. bark extract (FAB) in vitro and in vivo against Aβ-aggregation and aluminium induced-neurotoxicity in mice. FAB was characterized by colorimetric methods and its individual compounds were identified and quantified by LC-MS. First, the neuroprotective effect of FAB was evaluated against Aβ25-35-aggregation where it was directly incubated with Aβ25-35 and the kinetic of aggregation was measured by spectrophotometer at 200 nm. Then, the extract was tested against Aβ25-35-induced cytotoxicity on PC12 cells and the cells viability was determined by MTT test. On the other hand, FAB (0.01 - 0.5 mg/mL) was tested against aluminium-activated lipid peroxidation in mice synaptosomal membranes, and in vivo against aluminium-caused neurotoxicity in male N.M.R.I. (Naval Medical Research Institute) mice; this test consisted of daily co-administration of the extract with Al for 60 days. At the end of the treatment, behavioral and memory tests (locomotor activity, black and white and Morris water maze tests) and histological analysis were realized. The identification and quantification of FAB phenolics revealed the presence of different phenolic classes with high concentration of phenylethanoids and hydroxycoumarins. FAB showed a high Aβ25-35 anti-aggregative effect and a dose dependent protective effect on PC12 cells. The extract also demonstrated a significant inhibition of lipid peroxidation and was found to prevent the Al harmful effects where it significantly increased the locomotor activity, decreased the anxiety, improved memory and reduced histological alterations. In conclusion, FAB is rich of bioactive compounds that gave it the ability to inhibit Aβ-aggregation and Al-caused neurotoxicity in mice.

RevDate: 2020-07-09

Ghanbari-Maman A, Ghasemian-Roudsari F, Aliakbari S, et al (2019)

Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex.

Iranian journal of pharmaceutical research : IJPR, 18(3):1466-1476.

Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer's disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic reticulum (ER) stress. This study was designed to examine hippocampal ER stress following EC amyloidopathy. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 μg of isradipine, nimodipine, or placebo over one week. Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus by colorimetric spectrophotometer. Aβ treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GSH level in the hippocampus decreased in the Aβ treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.

RevDate: 2020-07-06

Zhang R, Zhang JL, Li BT, et al (2020)

[Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 45(11):2601-2610.

Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of &quot;absorbed composition-target-pathway-disease&quot; was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a &quot;multi-ingredients-multi-targets and multi-pathways&quot; mode, providing a scientific basis for further drug research and development.

RevDate: 2020-07-06

Zhao T, Hu Y, Zang T, et al (2020)

Identifying Protein Biomarkers in Blood for Alzheimer's Disease.

Frontiers in cell and developmental biology, 8:472.

Background: At present, the main diagnostic methods for Alzheimer's disease (AD) are positron emission tomography (PET) scanning of the brain and analysis of cerebrospinal fluid (CSF) sample, but these methods are expensive and harmful to patients. Recently, more researchers focus on diagnosing AD by detecting biomarkers in blood, which is a cheaper and harmless way. Therefore, identifying AD-related proteins in blood can help treatment and diagnosis. Methods: We proposed a hypothesis that similar diseases share similar proteins. Diseases with similar symptoms are caused by abnormalities of similar proteins. Assuming that the similarities between AD and other diseases obey the normal distribution, we developed an iterative method based on disease similarity (IBDS). We combined Elastic Network (EN) with Minimum angle regression (MAR) to find the optimal solution. Finally, we used case studies and Summary data Mendelian Random (SMR) to verify our method. Results: We selected 39 diseases which are highly related to AD. They correspond 1,481 kinds of proteins. One hundred and eighty-four proteins are reported to be related to AD in Uniprot and the number would be 284 with our method. The AUC of our method by cross-validation is 0.9251 which is much higher than previous methods. Conclusion: In this paper, we presented a novel method for prioritizing AD-related proteins. Seven proteins have tissue specificity in blood among these 284 proteins, which could be used to diagnose AD in future. Case studies and SMR have been used to prove the relationship between these 7 proteins and AD. Availability and Implementation: https://github.com/zty2009/Identifying-Protein-Biomarkers-in-Blood-for-Alzheimer-s-Disease.

RevDate: 2020-07-06

Jahangard Y, Monfared H, Moradi A, et al (2020)

Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer's Disease.

Frontiers in neuroscience, 14:564.

Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)-based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood-brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl-2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ-treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29-containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.

RevDate: 2020-07-05

Shi Y, Zhang L, Gao X, et al (2020)

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.

Journal of Alzheimer's disease : JAD pii:JAD200227 [Epub ahead of print].

BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.

METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration.

RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice.

CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

RevDate: 2020-07-04

Bhandari RK, Wang X, Saal FSV, et al (2020)

Transcriptome analysis of testis reveals the effects of developmental exposure to bisphenol a or 17α-ethinylestradiol in medaka (Oryzias latipes).

Aquatic toxicology (Amsterdam, Netherlands), 225:105553 pii:S0166-445X(20)30303-9 [Epub ahead of print].

Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 μg/L) or EE2 (0.01 μg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.

RevDate: 2020-07-03

Alam J, Jaiswal V, L Sharma (2020)

Screening of Antibiotics against β-amyloid as Anti-amyloidogenic Agents: A Drug Repurposing Approach.

Current computer-aided drug design pii:CAD-EPUB-107878 [Epub ahead of print].

BACKGROUND: β-amyloid (Aβ) production and aggregation is the main culprit of Alzheimer's disease (AD). AD is becoming crisis where no treatment available for halting the disease progression. Antibiotics are used not only to treat infections, but also some of the non-contagious diseases and have found active as anti-amyloidogenic agents.

OBJECTIVE: The work aim's to investigate anti-amyloidogenic activity of antibiotics as re-purposing agents via inhibiting Aβ aggregation and fibril formation employing in-silico and in-vitro approaches. Mehtods: In-silico screening was designed with receptor and ligand preparation, grid formation, docking simulation and its analysis. Thioflavin T-amyloid binding and protease-digestion studies were intended as in-vitro assays. The pharmacological potential of antibiotics as anti-amyloidogenic agents was assessed by these methods.

RESULTS: Paromomycin and Neomycin were identified with higher order of estimated free energy of binding in in-silico sreening. In in-vitro screening, paromomycin significantly (p<0.01) reduced the fluorescence intensity and resistance to tryptic degradation of Aβ(1-42) peptides while neomycin had no or little effect (p<0.01) when compared to control. Results from docking and wet lab studies were found in correlation.

CONCLUSION: Paromomycin exhibited higher anti-Aβ aggregating and defibrillogenic activity than neomycin and leaves an indication for further in-vivo testing and could be a future promising anti-amyloidal candidate for the treatment of several amyloidoses.

RevDate: 2020-07-03

Schwartz L, Peres S, Jolicoeur M, et al (2020)

Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders.

Biogerontology pii:10.1007/s10522-020-09888-6 [Epub ahead of print].

Alzheimer's disease (AD) and cancer have much in common than previously recognized. These pathologies share common risk factors (inflammation and aging), with similar epidemiological and biochemical features such as impaired mitochondria. Metabolic reprogramming occurs during aging and inflammation. We assume that inflammation is directly responsible of the Warburg effect in cancer cells, with a decreased oxidative phosphorylation and a compensatory highthroughput glycolysis (HTG). Similarly, the Warburg effect in cancer is thought to support an alkaline intracellular pH (pHi), a key component of unrelenting cell growth. In the brain, inflammation results in increased secretion of lactate by astrocytes. The increased uptake of lactic acid by neurons results in the inverse Warburg effect, such as seen in AD. The neuronal activity is dampened by a fall of pHi. Pronounced cytosol acidification results in decreased mitochondrial energy yield as well as apoptotic cell death. The link between AD and cancer is reinforced by the fact that treatment aiming at restoring the mitochondrial activity have been experimentally shown to be effective in both diseases. Low carb diet, lipoic acid, and/or methylene blue could then appear promising in both sets of these clinically diverse diseases.

RevDate: 2020-07-02

Lau YCC, Ding JA, Simental A, et al (2020)

Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

RevDate: 2020-07-01

Yu L, Tasaki S, Schneider JA, et al (2020)

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.

JAMA psychiatry pii:2767297 [Epub ahead of print].

Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.

Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.

This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.

Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.

Main Outcomes and Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.

Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.

Conclusions and Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.

RevDate: 2020-06-30

Zhang Z, Kang D, H Li (2020)

Testosterone and Cognitive Impairment or Dementia in Middle-Aged or Aging Males: Causation and Intervention, a Systematic Review and Meta-Analysis.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

BACKGROUND AND PURPOSE: To investigate the association between testosterone levels and the risk of dementia and to assess the effectiveness of testosterone supplement treatment in patients with cognitive impairment or dementia.

METHODS: We searched Pubmed, Cochrane Library, and EMBASE on September 30, 2019.

RESULTS: The risk factor portion of the review included 27 studies with 18 599 participants. Studies revealed inconsistent findings on the association between testosterone levels and the risk of all-cause dementia or Alzheimer disease (AD). The result from our meta-analysis showed an increased risk of all-cause dementia with decreasing total testosterone (total-T, 4572 participants, hazard ratio: 1.14, 95% CI: 1.04-1.26). Some studies also found an increased risk of AD with a lower level of total-T, free testosterone, and bioavailable testosterone. Testosterone supplement treatment may improve general cognitive function and motor response in the short term as measured by the Developmental Test of Visual-Motor Integration (mean difference [MD]: 4.4, 95% CI: 1.20-7.59) and the Mini-Mental State Examination (MD: 3.4, 95% CI: 0.83-5.97) and verbal memory as measured by story recall delay at 3 months (MD: 8.4, 95% CI: 0.49-16.3).

CONCLUSION: Lower levels of testosterone may be associated with an increased risk of all-cause dementia or AD. Testosterone supplement treatment may or may not improve general cognitive function in patients with cognitive impairment/AD.

RevDate: 2020-06-30

Park KH, Lim JS, Seo SW, et al (2020)

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.

Dementia and neurocognitive disorders, 19(2):39-53.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

RevDate: 2020-06-30

Iloun P, Hooshmandi E, Gheibi S, et al (2020)

Roles and Interaction of the MAPK Signaling Cascade in Aβ25-35-Induced Neurotoxicity Using an Isolated Primary Hippocampal Cell Culture System.

Cellular and molecular neurobiology pii:10.1007/s10571-020-00912-4 [Epub ahead of print].

Alzheimer's disease (AD) is characterized with increased formation of amyloid-β (Aβ) in the brain. Aβ peptide toxicity is associated with disturbances of several intracellular signaling pathways such as mitogen activated protein kinases (MAPKs). The aim of this study was to investigate the role of MAPKs and their interactions in Aβ-induced neurotoxicity using isolated hippocampal neurons from the rat. Primary hippocampal cells were cultured in neurobasal medium for 4 days. Cells were treated with Aβ25-35 and/or MAPKs inhibitors for 24 h. Cell viability was determined by an MTT assay and phosphorylated levels of P38, JNK, and ERK were measured by Western blots. Aβ treatment (10-40 µM) significantly decreased hippocampal cell viability in a dose-dependent manner. Inhibition of P38 and ERK did not restore cell viability, while JNK inhibition potentiated the Aβ-induced neurotoxicity. Compared to the controls, Aβ treatment increased levels of phosphorylated JNK, ERK, and c-Jun, while it had no effect on levels of phosphorylated P38. In addition, P38 inhibition led to decreased expression levels of phosphorylated ERK; inhibition of JNK resulted in decreased expression of c-Jun; and inhibition of ERK, decreased phosphorylated levels of JNK. These results strongly suggest that P38, ERK, and JNK are not independently involved in Aβ-induced toxicity in the hippocampal cells. In AD, which is a multifactorial disease, inhibiting a single member of the MAPK signaling pathway, does not seem to be sufficient to mitigate Aβ-induced toxicity and thus their interactions with each other or potentially with different signaling pathways should be taken into account.

RevDate: 2020-06-29

Grammatikopoulou MG, Goulis DG, Gkiouras K, et al (2020)

To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease.

Advances in nutrition (Bethesda, Md.) pii:5864685 [Epub ahead of print].

Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs, MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer's Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019128311.

RevDate: 2020-06-29

Ugrumov M (2020)

Development of early diagnosis of Parkinson's disease: Illusion or reality?.

CNS neuroscience & therapeutics [Epub ahead of print].

The fight against neurodegenerative diseases, Alzheimer disease and Parkinson's disease (PD), is a challenge of the 21st century. The low efficacy of treating patients is due to the late diagnosis and start of therapy, after the degeneration of most specific neurons and depletion of neuroplasticity. It is believed that the development of early diagnosis (ED) and preventive treatment will delay the onset of specific symptoms. This review evaluates methodologies for developing ED of PD. Since PD is a systemic disease, and the degeneration of certain neurons precedes that of nigrostriatal dopaminergic neurons that control motor function, the current methodology is based on searching biomarkers, such as premotor symptoms and changes in body fluids (BF) in patients. However, all attempts to develop ED were unsuccessful. Therefore, it is proposed to enhance the current methodology by (i) selecting among biomarkers found in BF in patients at the clinical stage those that are characteristics of animal models of the preclinical stage, (ii) searching biomarkers in BF in subjects at the prodromal stage, selected by detecting premotor symptoms and failure of the nigrostriatal dopaminergic system. Moreover, a new methodology was proposed for the development of ED of PD using a provocative test, which is successfully used in internal medicine.

RevDate: 2020-06-29

Salimi A, Gobadian H, B Sharif Makhmal Zadeh (2020)

Dermal Pharmacokinetics of rivastigmine-loaded liposomes: an Ex vivo- in vivo correlation study.

Journal of liposome research [Epub ahead of print].

The aim of the present study was to develop a topical liposomal formulation as a transdermal delivery of rivastigmine for the treatment of Alzheimer disease as an alternative to the oral dosage form and to achieve smooth continuous drug delivery and maintain plasma levels within the therapeutic window. Rivastigmine-loaded liposomes were prepared by a thin layer hydration technique that was applied in Ex vivo- in vivo correlation study. Permeability parameters through rat skin in Ex vivo study and pharmacokinetic parameters in the in-vivo study were evaluated. The Ex vivo permeation study showed that liposomes provided steady-state flux 0.11 ± 0.01 mg/cm.h that was more than 2-fold the aqueous control. In the in vivo experiments, after topical application of optimized rivastigmine liposomes, the Cmax 208 ng/ml and AUC0-24 3605 (ng.h/ml) were also significantly higher than the control group (both P < 0.01). A point-to-point significant linear correlation was found between ex vivo- in vivo parameters, meaning in vivo pharmacokinetic parameters can be predicted by Ex vivo permeation parameters. These data suggest that a liposomal formulation could be an effective carrier to enhance rivastigmine permeation through the skin and maintain plasma levels within the therapeutic window.

RevDate: 2020-06-28

Volicer L (2020)

Physiological and pathological functions of beta-amyloid in the brain and alzheimer's disease: A review.

The Chinese journal of physiology, 63(3):95-100.

Alzheimer's disease is a major health problem all over the world. The role of beta-amyloid (Aβ) is at the center of investigations trying to discover the disease pathogenesis and to develop drugs for treatment or prevention on Alzheimer's disease. This review summarizes both physiological and pathological functions of Aβ and factors that may participate in the disease development. Known genetic factors are trisomy of chromosome 21, mutations of presenilin 1 and 2, and apolipoprotein E4. Lifetime stresses that increase the risk of development of Alzheimer's disease are described. Another important factor is the level of education, especially of linguistic ability. Lifestyle factors include mental and physical exercise, head injury, social contacts, and diet. All these factors might potentiate the effect of aging on the brain to increase the risk of development of pathological changes. The review summarizes pathological features of Alzheimer brain, Aβ plaques, neurofibrillary tangles composed of hyperphosphorylated tau, and brain atrophy. Consequences of Alzheimer's disease that are reviewed include cognitive deficit, loss of function, and neuropsychiatric symptoms. Because there is no effective treatment, many persons with Alzheimer's disease survive to severe and terminal stages which they may fear. Alzheimer's disease at this stage should be considered a terminal disease for which palliative care is indicated. Importance of advance directives, promoting previous wishes of the person who was developing dementia and who subsequently lost decision-making capacity, and limitations of these directives are discussed. Information in this review is based on author's knowledge and clinical experience that were updated by searches of PubMed.

RevDate: 2020-06-27

Berezutsky MA, Durnova NA, Andronova TA, et al (2020)

[Alzheimer's disease: experimental and clinical researches of Chinese herbal medicine neurobiological effects (a review).].

Advances in gerontology = Uspekhi gerontologii, 33(2):273-281.

The analysis of experiments and clinical data about research of neurobiological effects of chinese herbal medicine, which is used by Alzheimer`s disease treatment, was presented in given overview. The rats with injection of Aβ1-42 or Aβ25-35 peptides, or ibotenic acid, or streptozotocin as well as the natural line of mice SAMP8 with the phenotype of accelerated aging and other were used as the experimental models of Alzheimer`s disease. Various neurobiological effects of various herbal decoctions in the cells of hippocampus were demonstrated - the inhibition of amyloid β peptides aggregation, increasing of neurons quantity with normal morphology and decreasing of apoptotic cells, decreasing of inducible nitric oxide synthase (iNOS) production, decreasing of reactive expression level of RAGE and increasing reactive expression level of LRP-1, decreasing of tau protein phosphorylation at Thr231 and Ser422, inhibition of expression of GSK-3β and CDK-5, decreasing of activation and inflammation of microglia, production of 15 types of N-glycans in the cerebral cortex layers, which are absent in experimental animals. The improvement of memorization and training abilities was established.

RevDate: 2020-06-25

Hung A, Schneider M, Lopez MH, et al (2020)

Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.

Journal of managed care & specialty pharmacy, 26(7):888-900.

The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.

RevDate: 2020-06-24

Sut S, Maggi F, Bruno S, et al (2020)

Hairy Garlic (Allium subhirsutum) from Sicily (Italy): LC-DAD-MSn Analysis of Secondary Metabolites and In Vitro Biological Properties.

Molecules (Basel, Switzerland), 25(12): pii:molecules25122837.

Allium subhirsutum, known as hairy garlic, is a bulbous plant widespread in the Mediterranean area and locally used as a food and spice. In the present study, the chemical profile of the ethanolic extracts from bulbs (BE) and aerial parts (APE) were analyzed by HPLC-ESI-MSn, and antioxidant properties were evaluated by DPPH, ABTS and TEAC assays. The traditional use in the diet, and the well documented biological activity of Allium species suggest a potential as a new nutraceutical. For this reason, the potential usefulness of this food can be considered in the treatment and prevention of degenerative Alzheimer disease. For this reason, acetylcholinesterase inhibitory property was investigated. Furthermore, due to the observed presence of sulfur-containing and phenolic constituents, the cytotoxicity on tumor cells line was investigated. Results revealed significant AChE inhibitory activity for BE and APE. Both extracts exhibited also moderate antioxidant properties in the in vitro assays. Finally, limited cytotoxic activity was observed towards Human colon carcinoma and adenocarcinoma cell line, with differences between the individual parts tested. HPLC-ESI-MSn analysis showed that hairy garlic is a good source of sulphur compounds, flavonoids and phenylpropanoids derivatives, thus being a valid alternative to the common garlic (A. sativum). This work opens new opportunities for the application of A. subhirsutum as a health-promoting food.

RevDate: 2020-06-24

Stracke S, Lange S, Bornmann S, et al (2020)

Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor-Rationale and Design of the IMAD Pilot Study.

Journal of clinical medicine, 9(6): pii:jcm9061919.

BACKGROUND: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer's clinical syndrome within a one-year follow-up period.

METHODS: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19-26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months.

CONCLUSION: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer's clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.

RevDate: 2020-06-26

Sivera R, Capet N, Manera V, et al (2020)

Voxel-based assessments of treatment effects on longitudinal brain changes in the Multidomain Alzheimer Preventive Trial cohort.

Neurobiology of aging, 94:50-59 pii:S0197-4580(20)30131-7 [Epub ahead of print].

The Multidomain Alzheimer Preventive Trial was designed to assess the effect of omega-3 supplementation and multidomain intervention on cognitive decline of subjects with subjective memory complaint. In terms of cognitive testing, no significant effect was found. In this paper, we evaluate the effect of the interventions on the brain morphological changes. Subjects with magnetic resonance imaging acquisitions at baseline and at 36 months were included (N = 376). Morphological changes were characterized by volume measurements and nonlinear deformation. The multidomain intervention was associated with a significant effect on the 3-year brain morphological changes in the deformation-based approach. Differences were mainly located in the left periventricular area next to the temporoparietal junction. These changes were associated with better cognitive performance and mood/behavior stabilization. No effect of the omega-3 supplementation was observed. This result suggests a possible effect on cognition, not yet observable after 3 years. We argue that neuroimaging could help define whether early intervention strategies are effective to delay cognitive decline and dementia.

RevDate: 2020-06-25

Craft S, Raman R, Chow TW, et al (2020)

Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial.

JAMA neurology [Epub ahead of print].

Importance: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial.

Objective: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial.

A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019.

Interventions: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices.

Main Outcomes and Measures: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months.

Results: A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment.

Conclusions and Relevance: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort.

Trial Registration: ClinicalTrials.gov Identifier: NCT01767909.

RevDate: 2020-06-25

Raghavan NS, Dumitrescu L, Mormino E, et al (2020)

Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.

JAMA neurology [Epub ahead of print].

Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.

Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.

Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels.

Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.

Conclusions and Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

RevDate: 2020-06-20

Gupta SD, CH Pan (2020)

Recent update on discovery and development of Hsp90 inhibitors as senolytic agents.

International journal of biological macromolecules pii:S0141-8130(20)33560-1 [Epub ahead of print].

Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone are also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed.

RevDate: 2020-06-20

Abou Baker DH, Ibrahim BMM, Hassan NS, et al (2020)

Exploiting Citrus aurantium seeds and their secondary metabolites in the management of Alzheimer disease.

Toxicology reports, 7:723-729.

Fruit by-products are considered nature's golden gift for human health and a good starting point to discover new drugs depending on the fact that they contain millions of bio-active compounds that are responsible for therapeutic activities. In this context, the main goal of this study is to recycle Citrus aurantium (C. aurantium) seeds to produce pharmaceutical molecules to be used in the prevention of the progressive neurological damage associated with Alzheimer disease (AD). Donepezil (0.75 mg/kg), hesperidin (125 and 250 mg/kg) and limonoids (50 and 100 mg/kg) were used for treatment of rats for 2 weeks prior to concomitant administration of AlCl3 for three successive weeks. Protection against cognitive deterioration was observed among study group with insignificant difference from normal control group and significant difference from positive control group in the Y-Maze test. On the other hand, treatment with both doses of hesperidin (125 and 250 mg/kg) and high dose of limonoids only (100 mg/kg) produced improvement in psychological state, observed by significant increase in ambulation frequency in comparison to positive control group, however it was not as frequent as normal group, as it was significantly less than normal group in the open field test. Regarding acetylcholine esterase (AChE) and beta-amyloid (β amyloid) levels, the effect of limonoids low dose was the best as it didn't have a significant effect when compared to normal control, also hesperidin in both doses showed insignificant effects on β amyloid levels when compared to normal control group. Our results encourage the use of C. aurantium seeds which are wasted in huge amounts, as Alzheimer prophylactic food additives.

RevDate: 2020-06-19

Loeffler DA (2020)

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Frontiers in neurology, 11:459.

Grifols' recent Alzheimer Management by Albumin Replacement ("AMBAR") study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

RevDate: 2020-06-19

Rea S, Della-Morte D, Pacifici F, et al (2020)

Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells.

Frontiers in pharmacology, 11:779.

Patients with diabetes mellitus (DM) are more prone to develop cognitive decline and neurodegenerative diseases. A pathological association between an autosomal dominant neurological disorder caused by brain accumulation in mutated huntingtin (mHTT), known as Huntington disease (HD), and DM, has been reported. By using a diabetic mouse model, we previously suggested a central role of the metabolic pathways of HTT, further suggesting the relevance of this protein in the pathology of DM. Furthermore, it has also been reported that intranasal insulin (Ins) administration improved cognitive function in patients with neurodegenerative disorders such as Alzheimer disease, and that exendin-4 (Ex-4) enhanced lifespan and ameliorated glucose homeostasis in a mouse model of HD. Although antioxidant properties have been proposed, the underlying molecular mechanisms are still missing. Therefore, the aim of the present study was to investigate the intracellular pathways leading to neuroprotective effect of Ins and Ex-4 hypoglycemic drugs by using an in vitro model of HD, developed by differentiated dopaminergic neurons treated with the pro-oxidant neurotoxic compound 6-hydroxydopamine (6-ohda). Our results showed that 6-ohda increased mHTT expression and reduced HTT phosphorylation at Ser421, a post-translational modification, which protects against mHTT accumulation. Pre-treatment with Ins or Ex-4 reverted the harmful effect induced by 6-ohda by activating AKT1 and SGK1 kinases, and by reducing the phosphatase PP2B. AKT1 and SGK1 are crucial nodes on the Ins activation pathway and powerful antioxidants, while PP2B dephosphorylates HTT contributing to mHTT neurotoxic effect. In conclusion, present results highlight that Ins and Ex-4 may counteract the neurotoxic effect induced by mHTT, opening novel pharmacological therapeutic strategies against neurodegenerative disorders, with the main focus on HD, still considered an orphan illness.

RevDate: 2020-06-26

Aghajanzadeh M, Andalib S, Danafar H, et al (2020)

The effect of baicalein-loaded Y-shaped miktoarm copolymer on spatial memory and hippocampal expression of DHCR24, SELADIN and SIRT6 genes in rat model of Alzheimer.

International journal of pharmaceutics, 586:119546 pii:S0378-5173(20)30530-5 [Epub ahead of print].

In the present study, we successfully synthesized nanocarriers (NCs) based on Y-shaped miktoarm copolymers, Poly Ethylene Glycol-Lysine-(Poly Caprolactone)2 (PEG-Lys-PCL2), which were loaded by baicalein (B) through the nanoprecipitation process to assess their in-vitro and in-vivo properties. We applied various methods and measurements including proton nuclear magnetic resonance (HNMR), dynamic light scattering (DLS), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), MTT assay, hemolysis test, lethal dose, real-time PCR, and Morris water maze. The results of DLS indicated that the size and zeta potential of the obtained NCs and B-loaded NCs were acceptable. Also, in-vivo and in-vitro biocompatibility examinations proved that miktoarm-based NCs were safe, and all rats treated with miktoarm-based NCs did not exhibit any remarkable weight loss during the experiment. The results of the Morris water maze (in-vivo test) revealed that the normal saline-treated group, as well as B-miktoarm + Scopolamine (M + B + S) and B-miktoarm-Tween80 + Scopolamine (M + B + T + S) pretreatment groups, spent more time in the target quadrant. Thus, this experiment showed that pretreatment of rats with M + B + S and M + B + T + S had the most effects on spatial memory. According to quantitative PCR analysis, we hypothesized that, in comparison with other experimental groups, pretreatment of rats with M + B + T + S could be more effective in preventing cholinergic dysfunction, brain oxidative stress and cognitive deficits which cause by Scopolamine HBr. This outcome may be partially due to the upregulation of DHCR24, SELADIN, and SIRT6 in entire of the hippocampal region of normal saline-treated and M + B + T + S pretreatment groups. These results may be because mimicking the cell membrane structure would be an excellent feature for miktoarm, and partial coating of Tween-80 can play a critical role for PEG-Lys-PCL2-based NCs in crossing the brain cell membrane, and they can easily be uptaken by the cells. Eventually, all of the obtained data confirmed that PEG-Lys-PCL2 miktoarm star copolymers are suitable for delivering therapeutic agents to the brain for the treatment of Alzheimer's disease (AD). Also, it seems that baicalein should be taken into account as a potent compound for the treatment of AD.

RevDate: 2020-06-13

Gandhidasan S, Reddy CA, Woody NM, et al (2020)

Outpatient Anesthesia Facilitates Stereotactic Body Radiation Therapy for Early Stage Lung Cancer Patients With Advanced Cognitive Impairments.

Advances in radiation oncology, 5(3):444-449.

Purpose: To report on the use of outpatient anesthesia (OPA) facilitating delivery of stereotactic body radiation therapy (SBRT) in patients with severe cognitive impairments (CI) diagnosed with inoperable early stage lung cancer.

Methods and Materials: We surveyed our institutional review board-approved prospective lung SBRT data registry to document the feasibility of using anesthesia in CI patients and to determine their SBRT outcomes.

Results: From 2004 to 2018, 8 from a total 2084 patients were identified for this analysis. The median age at treatment was 68 years (range, 44-78). Most patients were female (62.5%). CI diagnoses included Alzheimer-related dementia (3 patients), chronic schizophrenia (3 patients), severe anxiety disorder (1 patient), and severe developmental disability (1 patient). The median tumor size was 3.4 cm (range, 1.1-10.5), and 7 patients (87.5 %) had central lesions. The median follow-up time was 22.5 months. The most common (50%) SBRT schedule used was 50 Gy in 5 fractions. Intravenous propofol (10 mg/mL) was used for OPA in all cases at the time of simulation and with daily treatments. OPA was well tolerated and all patients completed SBRT as prescribed. There was one grade 5 but no other grade 3 or higher SBRT-related toxicities. One patient died with local failure and one of distant failure.

Conclusions: OPA made lung SBRT feasible for patients with CIs. SBRT outcomes were in keeping with those reported in the literature. CI should not be considered a contraindication per se to SBRT delivery in patients otherwise appropriate for this modality.

RevDate: 2020-06-13

Alamro AA, Alsulami EA, Almutlaq M, et al (2020)

Therapeutic Potential of Vitamin D and Curcumin in an In Vitro Model of Alzheimer Disease.

Journal of central nervous system disease, 12:1179573520924311.

Background: Alzheimer disease is a progressive neurodegenerative disease, affecting a very high proportion of the aging population. Several studies have demonstrated that one of the main contributors to this disease is oxidative stress (OS), which causes peroxidation of protein, lipids, and DNA resulting in the formation of advanced glycosylated end products (AGE) in the brain tissues. These AGE are usually associated with the amyloid β (Aβ), which could further aggravate its toxicity and its clearance. Antioxidants counteract the deterioration caused by OS.

Objective: We aimed to evaluate the effect of vitamin D3 and curcumin on primary cortical neuronal cultures exposed to Aβ1-42 toxicity for different time periods.

Methods: Primary cortical neuronal cultures were set up and exposed to Aβ1-42 for up to 72 hours. Cell viability was studied by 3[4,5-dimethylthiazole-2-yl]-2,5-dipheyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Biochemical assays for OS such as lipid peroxidation, reduced Glutathione(GSH), Glutathione S-transferase (GST), catalase, and superoxide dismutase (SOD) were conducted. Sandwich enzyme-linked immunosorbent assay (ELISA) was used to study the neurotrophic growth factor (NGF) expression.

Results: Treatments with Aβ1-42 caused an elevation in lipid peroxidation products, which were ameliorated in the presence of vitamin D3 and curcumin. Both enzymatic (GST, catalase, and SOD) and nonenzymatic antioxidants (reduced GSH) were raised significantly in the presence of vitamin D3 and curcumin, which resulted in the better recovery of neuronal cells from Aβ1-42 treatment. Treatment with vitamin D3 and curcumin also resulted in the upregulation of NGF levels.

Conclusions: This study suggests that vitamin D3 and curcumin can be a promising natural therapy for the treatment of Alzheimer disease.

RevDate: 2020-06-11

Tang KS (2020)

Protective Effects of Polydatin Against Dementia-Related Disorders.

Current neuropharmacology pii:CN-EPUB-107282 [Epub ahead of print].

Dementia is a collection of symptoms affecting a person's cognition. Dementia is debilitating, and therefore, finding an effective treatment is of the utmost importance. Resveratrol, which exhibits neuroprotective effects, has low bioavailability. However, it's glucoside polydatin is more bioavailable. Here, the evidence that supports the protective role of polydatin against dementia-related diseases such as Alzheimer's disease, vascular dementia, alcohol-related dementia, and Lewy body dementias is presented. The beneficial effects of polydatin from a mechanistic perspective are specifically emphasized in this review. Future directions in this area of research are also discussed.

RevDate: 2020-06-12

Ordóñez-Gutiérrez L, F Wandosell (2020)

Nanoliposomes as a Therapeutic Tool for Alzheimer's Disease.

Frontiers in synaptic neuroscience, 12:20.

The accumulation of extracellular amyloid-beta (Aβ), denoted as senile plaques, and intracellular neurofibrillary tangles (formed by hyperphosphorylated Tau protein) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). The current and most accepted hypothesis proposes that the oligomerization of Aβ peptides triggers the polymerization and accumulation of amyloid, which leads to the senile plaques. Several strategies have been reported to target Aβ oligomerization/polymerization. Since it is thought that Aβ levels in the brain and peripheral blood maintain equilibrium, it has been hypothesized that enhancing peripheral clearance (by shifting this equilibrium towards the blood) might reduce Aβ levels in the brain, known as the sink effect. This process has been reported to be effective, showing a reduction in Aβ burden in the brain as a consequence of the peripheral reduction of Aβ levels. Nanoparticles (NPs) may have difficulty crossing the blood-brain barrier (BBB), initially due to their size. It is not clear whether particles in the range of 50-100 nm should be able to cross the BBB without being specifically modified for it. Despite the size limitation of crossing the BBB, several NP derivatives may be proposed as therapeutic tools. The purpose of this review is to summarize some therapeutic approaches based on nanoliposomes using two complementary examples: First, unilamellar nanoliposomes containing Aβ generic ligands, such as sphingolipids, gangliosides or curcumin, or some sphingolipid bound to the binding domain of ApoE; and second, nanoliposomes containing monoclonal antibodies against Aβ. Following similar rationale NPs of poly(lactide-co-glycolide)-poly (ethylene glycol) conjugated with curcumin-derivate (PLGA-PEG-B6/Cur) were reported to improve the spatial learning and memory capability of APP/PS1 mice, compared with native curcumin treatment. Also, some new nanostructures such as exosomes have been proposed as a putative therapeutic and prevention strategies of AD. Although the unquestionable interest of this issue is beyond the scope of this review article. The potential mechanisms and significance of nanoliposome therapies for AD, which are still are in clinical trials, will be discussed.

RevDate: 2020-06-22

Kinfe T, Stadlbauer A, Winder K, et al (2020)

Incisionless MR-guided focused ultrasound: technical considerations and current therapeutic approaches in psychiatric disorders.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: MR-guided focused ultrasound operating at higher intensities have been reported to effectively and precisely ablate deeper brain structures like the basal ganglia or the thalamic nuclei for the treatment of refractory movement disorders, neuropathic pain and most recently neuropsychiatric disorders, while low-intensity focused ultrasound represents an approach promoting mechanical blood-brain-barrier opening and neuromodulation. This narrative review summarizes the technical development and the therapeutic potential of incisionless MRgFUS in order to treat neuropsychiatric disorders.

AREAS COVERED: A narrative review of clinical trials assessing the safety and efficacy of MRgFUS. A literature review was performed using the following search terms: MR-guided focused ultrasound, psychiatric disorders, noninvasive and invasive brain modulation/stimulation techniques.

EXPERT OPINION: MRgFUS ablation is under clinical investigation (unblinded study design) for obsessive-compulsive disorders (OCDs) [capsulotomy; ALIC] and depression/anxiety disorders [capsulotomy] and has demonstrated an improvement in OCD and depression, although of preliminary character. Low-intensity ultrasound applications have been explored in Alzheimer´s disease (phase 1 study) and healthy subjects. Currently, limited evidence hinders comparison and selection between MRgFUS and noninvasive/invasive brain modulation therapies. However, comparative, sham-controlled trials are needed to reexamine the preliminary findings for the treatment of psychiatric disorders.

RevDate: 2020-06-11

Weinberg MS, Patrick RE, Schwab NA, et al (2020)

Clinical Trials and Tribulations in the COVID-19 Era.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry [Epub ahead of print].

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.

RevDate: 2020-06-07

Ren B, Cheng F, Wang X, et al (2020)

"Possible mechanisms underlying treatment of Alzheimer's disease with Traditional Chinese Medicine: active components, potential targets and synthetic pathways of Bulao Elixir".

Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan, 40(3):484-496.

OBJECTIVE: To elucidate the mechanisms underlying the treatment of Alzheimer's disease (AD) with Traditional Chinese Medicine (TCM), by examining the active components, potential targets and synthetic pathways of Bulao Elixir (BLE).

METHODS: The Absorption, Distribution, Metabolism, Excretion (ADME) / Toxicology (T) calculation was used to screen the active components of Bulao Elixir. Based on the TCM Systems Pharmacology Analysis Platform (TCMSP database) and a text mining tool (GoPubMed database), we predicted and screened the active components of Bulao Elixir and its therapeutic targets for AD. Using the Database for Annotation, Visualization and Integrated Discovery (DAVID), we obtained the targets for AD. Cytoscape software was used to establish a network map of the active component-target and target-pathway of Bulao Elixir. Gene function, related biological processes and signaling pathways were analyzed using the DAVID database.

RESULTS: Twelve active components were selected from 196 components of Bulao Elixir. Among 2209 targets, 102 effective targets were selected, and 30 important targets were identified via matching with the disease targets. After further analysis, 14 core targets were identified. Enrichment analysis revealed that most of these important targets were involved in multiple biological processes, including apoptosis, inflammatory reactions, and cell regulation cycles. The synthetic pathways for AD treatment were identified after analyzing and confirming the relevant pathways, providing potentially useful information for diagnosis and treatment methods for AD.

CONCLUSION: The current study elucidated the potential treatment mechanisms of Bulao Elixir in AD using network pharmacology, providing a foundation for further clarification of its treatment targets.

RevDate: 2020-06-26

Mobed A, M Hasanzadeh (2020)

Biosensing: The best alternative for conventional methods in detection of Alzheimer's disease biomarkers.

International journal of biological macromolecules, 161:59-71 pii:S0141-8130(20)33424-3 [Epub ahead of print].

Conceivably the imperative reason for the absence of appropriate treatment for Alzheimer's disease (AD) is the late onset of clinical symptoms followed by late treatment. Specific biomarkers play a vital role in this area. The amyloid-beta peptide, tau protein and micRNA, are the most important biomarker associated in AD. There are many routine methods for identifying these biomarkers which molecular based methods with a high accuracy and sensitivity have been considered. These methods have some limitations such as; false positive and negative results, problem on the interpretation, complexity and time-consuming, high cost instruments and etc. To overcome these limitations, bioassays were developed extensively. There exist a multitude of possible applications for Alzheimer's disease biomarkers by using biosensors. This review mainly focuses on major biomarkers in Alzheimer's disease, routine and old methods in identifying biomarkers of AD and their advantages and limitation, and biosensors to the identification of amyloid beta, tau protein and micRNAs biomarkers. Furthermore, evaluation the strengths and weaknesses of the developed bioassays and introduce leading challenges are considered in this review.

RevDate: 2020-06-25
CmpDate: 2020-06-25

Chen KH, Chen HH, Li L, et al (2020)

The impact of exercise on patients with dementia: A 2-year follow-up.

Medicine, 99(23):e20597.

The current absence of a disease-modifying treatment for Alzheimer disease highlights the necessity for the benefits of nonpharmacological approaches. We aimed to investigate the effect of exercise in older patients with Alzheimer dementia.This is an observational, prospective cohort study in medical center. Eighty older patients with Alzheimer dementia, including 54 with mild dementia and 26 with moderate dementia, were followed up over 2 years. Patients were divided into exercise and no-exercise groups according to their weekly exercise habit. Mini-Mental State Examination (MMSE), clinical dementia rating (CDR), and senior fitness test were checked initially. We defined death and unexpected hospitalization as the outcomes.Age, sex, education years, and MMSE showed no significant differences between the groups (P > .05) in all patients. All the patients of the exercise group had significantly better left upper body strength, higher aerobic endurance, and left and right balance maintenance time than those of the no-exercise group (P < .05). There were no changes in hospitalization and mortality between the exercise and non-exercise groups during the 2-year follow-ups in all participants. However, in the mild and moderate dementia subgroups, age, sex, education years, and MMSE showed no significant differences between the groups (P > .05). The exercise group had significantly better lower body strength, left upper body strength, aerobic endurance, right upper body flexibility, lower body flexibility, balance maintenance, and agility than the no-exercise group in patients with mild dementia (P < .05). Moreover, the exercise group had significantly lesser unexpected hospitalization than the no-exercise group in the patients with mild dementia (P = .037).Despite the similarity in the status of dementia, exercise habit was found to be associated with a better senior fitness test score status. Hence, exercise can decrease unexpected hospitalization in patients with mild dementia but not those with total dementia.

RevDate: 2020-06-04

Ahmad R, Almubayedh H, Ahmad N, et al (2020)

Ethnobotany, ethnopharmacology, phytochemistry, biological activities and toxicity of Pistacia chinensis subsp. integerrima: A comprehensive review.

Phytotherapy research : PTR [Epub ahead of print].

Pistacia chinensis subsp. integerrima (J. L. Stewart ex Brandis) Rech. F. is a valuable medicinal plant used in south Asian communities for the treatment of asthma, diarrhea, diabetes, liver diseases, fever, pain and inflammation. This review critically evaluates the available information on P. integerrima's ethnobotany, ethnopharmacology, phytochemistry, pharmacology and toxicology. Electronic databases such as Google Scholar, PubMed, Springer Link, and so forth, books and theses were used to find relevant information about P. integerrima using keywords such as "Pistacia integerrima," "P. integerrima," "Ethnopharmacology," "Phytochemistry," "Traditional uses". A number of in vitro and in vivo pharmacological activities have been reported; however, the most promising and attractive activity observed was its role in Alzheimer, diabetes, convulsions, cancer, asthma, diabetes, diarrhea and as an immunomodulatory, analgesic and antiinflammatory. In addition, Pistagremic acid exerted anti-Alzheimer's activity based on a hitherto unknown mechanism through interference with the amyloidogenic pathway. Most of the pharmacological activities were linked with traditional uses. A range of compounds have been reported from P. integerrima extracts including triterpenes, volatile oils, flavonoids, fatty acids, phenolic, phytosterols, tannins and oligosaccharides as well as unknown triterpenes and flavonoids. Pistagremic acid, a novel triterpene, was attributed to most of the activities. in vivo toxicological studies in animal suggested a toxic dose of 1,500 mg kg-1 , for its methanolic extract. All reported pharmacological activities were carried out in vitro and a gap in research, that is, preclinical and clinical investigation exists. Its outstanding activity as an antiglycating agent is the most promising and a so far unique activity and needs further evaluation. In-depth research and clinical trials on human subjects in order to investigate P. integerrima pharmacological activity, clinical efficacy and safety are crucial next steps.

RevDate: 2020-06-03

Gao F, Zhang J, Ni T, et al (2020)

Herpud1 deficiency could reduce amyloid-β40 expression and thereby suppress homocysteine-induced atherosclerosis by blocking the JNK/AP1 pathway.

Journal of physiology and biochemistry pii:10.1007/s13105-020-00741-5 [Epub ahead of print].

Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

RevDate: 2020-06-23

Patel DV, Patel NR, Kanhed AM, et al (2020)

Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

Bioorganic chemistry, 101:103977 pii:S0045-2068(20)31113-5 [Epub ahead of print].

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aβ aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 μM) and BuChE (IC50 value of 1.29 μM), and significant inhibition of self-mediated Aβ1-42 aggregation (51.29% at 25 μM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aβ1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.

RevDate: 2020-06-26

Lorenzoni R, Davies S, Cordenonsi LM, et al (2020)

Lipid-core nanocapsules containing simvastatin improve the cognitive impairment induced by obesity and hypercholesterolemia in adult rats.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 151:105397 pii:S0928-0987(20)30186-X [Epub ahead of print].

The development of cognitive impairment may be related to high levels of plasma cholesterol and obesity. Simvastatin (SV) and lovastatin (LV) are drugs that can potentially be used for the treatment of cognitive deficit. This study aimed to develop and characterize lipid-core nanocapsules (LNC) containing SV (SV-LNC) or LV (LV-LNC), evaluating the effects of SV-LNC in an animal model of cognitive deficit. The formulations SV-LNC and LV-LNC presented a particle average size around 200 nm, a low-polydispersity index, and negative zeta potential. Analysis of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that there is no reaction among LNC components: LV was crystallized in the suspensions, and SV was molecularly dispersed. The encapsulation efficiency of the SV was high (98.9 ± 1.4%), while that of the LV was low (21.5 ± 1.5%).Based on these results, SV-LNC was used in the preclinical studies. Animals fed with a hyperlipidic diet (HD) developed obesity, hypercholesterolemia, and cognitive impairment, which was corroborated by the brain lesions indicated by histological analysis of some of the animals that received the high-fat diet. We observed that free simvastatin (CS3) was able to reduce the enzymatic activity of pyruvate kinase, an important enzyme for brain energy homeostasis, without affecting the memory of the animals that received a standard diet. However, it failed to improve the cognitive damage caused by a diet high in cholesterol and saturated fats. On the other hand, when simvastatin is "camouflaged" in the lipid-core nanocapsules (HNS3), this cognitive impairment improves. Thus, SV-LNC is a promising alternative therapy for the treatment of cognitive impairment.

RevDate: 2020-06-02

Inglet S, Winter B, Yost SE, et al (2020)

Clinical Data for the Use of Cannabis-Based Treatments: A Comprehensive Review of the Literature.

The Annals of pharmacotherapy [Epub ahead of print].

Objective: To compile and synthesize the available literature describing medical cannabis use across various disease states. Data Sources: PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords. Study Selection and Data Extraction: Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019. Data Synthesis: Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care. Relevance to Patient Care and Clinical Practice: Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria. Conclusions: As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.

RevDate: 2020-06-05

Molaei A, Hatami H, Dehghan G, et al (2020)

Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer's disease.

EXCLI journal, 19:596-612.

It has widely been reported that the brain in Alzheimer's disease (AD) is affected by increased oxidative stress, and this may have a role in the pathogenesis of this disorder. Quercetin, a polyphenol extensively found in nature, has recently been considered. Also, physical activities have a paradoxical effect on brain function in older adults. Therefore, this study aimed at investigating the synergic effects of quercetin (as chemical treatment) and exercise (as physical treatment) on AD-induced learning and memory impairment. Fifty-six adult male Wistar rats were randomly assigned into one of the following eight groups (n=7): The Control, Sham (saline), AD (intracerebroventricular administration of streptozotocin (STZ)), AD+80 mg/kg Quercetin (STZ+Q80), Quercetin vehicle (1 % Ethanol)+STZ, Exercise pretreatment (EX)+STZ, Off the treadmill+STZ, and EX+Q80+STZ. Quercetin administration was done intraperitoneally for 21 days after STZ injection. The rats ran on the treadmill for one hour a day for 60 days at a speed of 20-22 m/min. After the treatment, the spatial memory and levels of oxidative stress parameters were evaluated. The results showed that STZ caused spatial memory impairment and increased oxidative stress in the hippocampus. Exercise pretreatment or Quercetin injection improved the spatial memory impairment and oxidative stress caused by STZ injection. However, the combination of quercetin and exercise pretreatment was more effective. It can be concluded that the combined exercise pretreatment and Quercetin injection affected the antioxidant defense system and improved STZ-induced memory impairment.

RevDate: 2020-06-19

Ban JY, Park HK, SK Kim (2020)

Effect of Glycyrrhizic Acid on Scopolamine-Induced Cognitive Impairment in Mice.

International neurourology journal, 24(Suppl 1):S48-55.

PURPOSE: Cognitive impairment is one of the main symptoms of Alzheimer disease and other dementias. Glycyrrhiza uralensis is a natural product that has a protective effect against cognitive impairment. In this study, we investigated whether glycyrrhizic acid, among the main bioactive components of Glycyrrhiza uralensis, has a neuroprotective effect on scopolamine-induced cognitive impairment.

METHODS: Twenty-week-old male Institute of Cancer Research mice were used in this study. The scopolamine-induced cognitive impairment mice model was used. Glycyrrhizic acid was orally administered to mice once daily for 21 days, while scopolamine (1 mg/kg) treatment was delivered 30 minutes before behavioral tests. Donepezil (2 mg/kg) was used as a positive drug control. To evaluate the effect of glycyrrhizic acid, the following assessments were performed on hippocampal tissue: Y-maze test, acetylcholinesterase activity, antioxidant enzymes' activity (superoxide dismutase, catalase). Western blotting for phosphor-extracellular signal-regulated kinase, P38, and c-Jun NH2-terminal kinase was conducted.

RESULTS: We found that glycyrrhizic acid administration significantly improved scopolamine-induced cognitive impairment in the Y-maze test. The acetylcholinesterase activity, superoxide dismutase, and catalase activity in the glycyrrhizic acid-treated group showed a significant reversal of cognitive impairment compared with the scopolamine-treated group.

CONCLUSION: Our results suggest that glycyrrhizic acid has a neuroprotective effect on cognitive function in scopolamine-induced cognitive impairment.

RevDate: 2020-06-26

Chiu WT, Lee TY, Chan L, et al (2020)

Deep cerebral microbleeds are associated with poor cholinesterase inhibitor treatment response in people with Alzheimer disease.

Clinical neurology and neurosurgery, 195:105959 pii:S0303-8467(20)30302-4 [Epub ahead of print].

OBJECTIVES: Cholinesterase inhibitors (ChEIs) are the most effective treatment for Alzheimer disease (AD), but the response to treatment varies. Vascular lesions are associated with the pathogenesis of AD, and cerebral microbleeds (CMBs) are an indicator of hemorrhagic vascular pathology, which can be detected through susceptibility-weighted magnetic resonance imaging (SWMRI). This study investigated the association between CMBs and ChEI treatment response in patients with AD.

PATIENTS AND METHODS: We reviewed the medical records of 112 Taiwanese people with mild to moderate AD and at least 2 years of ChEI treatment between 2009 and 2016. Their baseline CMBs were quantified using the Microbleed Anatomical Rating Scale on SWMRI. Cognitive function of the patients was assessed using the Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI). Student t test and multivariable logistic regression were used to analyze the association between cognitive decline and CMBs.

RESULTS: The mean age of the study population was 76.0 ± 8.0 years. In total, 79 out of 112 patients were women. The presence of deep, but not lobar CMBs at baseline was associated with a significant cognitive decline according to the MMSE and CASI, particularly in long-term memory, attention, orientation, mental manipulation, and verbal fluency. Among deep CMBs, those in the basal ganglia and thalamus were significantly associated with cognitive decline.

CONCLUSIONS: Deep CMBs, particularly those in the basal ganglia and thalamus, but not lobar CMBs, are associated with poor response to ChEI treatment in people with AD. This can serve as a biomarker for predicting ChEI treatment response.

RevDate: 2020-05-31

de Oliveira FF, Chen ES, Smith MC, et al (2020)

Selected LDLR and APOE Polymorphisms Affect Cognitive and Functional Response to Lipophilic Statins in Alzheimer's Disease.

Journal of molecular neuroscience : MN pii:10.1007/s12031-020-01588-7 [Epub ahead of print].

Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.

RevDate: 2020-05-29

Revi M (2020)

Alzheimer's Disease Therapeutic Approaches.

Advances in experimental medicine and biology, 1195:105-116.

Alzheimer's disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906 (Hippius and Neundorfer, Dialogues Clin Neurosc 5:101-108, 2003). According to World Health Organization (WHO), AD is the most common cause of dementia, accounting for as many as 60-70% of senile dementia cases and affecting 47.5 million people worldwide (data from 2015) (Dementia Fact Sheet No 362. http://who.int/mediacentre/factsheets/fs362/en/). The median survival time after the onset of dementia ranges from 3.3 to 11.7 years (Todd et al. Int J Geriatr Psychiatry 28:1109-1124, 2013). AD is characterized as a severe, chronic, incurable, and progressive neurodegenerative disorder, associated with memory loss and cognition impairment accompanied by abnormal behavior and personality changes (Godyn et al. Pharmacol Rep 68:127-138, 2016). AD is characterized by neuronal death, which usually correlates with the appearance of key neuropathological changes, including acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of β-amyloid (Aβ plaques), intracellular neurofibrillary tangles by hyperphosphorylated tau protein deposits, neuroinflammation, and widespread neuronal loss (Godyn et al. Pharmacol Rep 68:127-138, 2016; Graham et al. Annu Rev. Med 68:413-430, 2017). The discovery of the degeneration of cholinergic neurons and the reduction of acetylcholine levels in postmortem studies of patients resulted in the use of drugs that leads to the increase of acetylcholine levels in brain (Dubois et al. Lacet Neurol 13:614-629, 2014). At present there is no preventative or curative treatment that interferes with the development of the disease. However, in recent years progress was made in the development of cholinergic drugs which have a positive effect on disease progression. Nowadays, specific drugs that can inhibit the enzyme that degrades acetylcholine are used. The development of new effective drugs involves a difficult and time-consuming process, accompanied by a very high failure rate. In the absence of effective therapies, the estimated number of people with dementia will reach 115 to 131, five million by 2050 (Dubois et al. Lacet Neurol 13:614-629, 2014; Cummings et al. Alzheimers Res Ther 6:37, 2014). Novel therapies and new targets required for developing more effective drugs for the treatment of AD patients are urgently needed.

RevDate: 2020-05-29

Ghatak S, Dolatabadi N, Gao R, et al (2020)

NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models.

Molecular psychiatry pii:10.1038/s41380-020-0776-7 [Epub ahead of print].

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

RevDate: 2020-06-19

Ornoy A, Becker M, Weinstein-Fudim L, et al (2020)

S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy.

International journal of molecular sciences, 21(10):.

S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.

RevDate: 2020-06-09

Maier F, Spottke A, Bach JP, et al (2020)

Bupropion for the Treatment of Apathy in Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 3(5):e206027.

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.

Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.

This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.

Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.

Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.

Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.

Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.

Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.

RevDate: 2020-06-21

Thomas NWD, Beattie Z, Marcoe J, et al (2020)

An Ecologically Valid, Longitudinal, and Unbiased Assessment of Treatment Efficacy in Alzheimer Disease (the EVALUATE-AD Trial): Proof-of-Concept Study.

JMIR research protocols, 9(5):e17603.

BACKGROUND: The current clinical trial assessment methodology relies on a combination of self-report measures, cognitive and physical function tests, and biomarkers. This methodology is limited by recall bias and recency effects in self-reporting and by assessments that are brief, episodic, and clinic based. Continuous monitoring of ecologically valid measures of cognition and daily functioning in the community may provide a more sensitive method to detect subtle, progressive changes in patients with cognitive impairment and dementia.

OBJECTIVE: This study aimed to present an alternative trial approach using a home-based sensing and computing system to detect changes related to common treatments employed in Alzheimer disease (AD). This paper introduces an ongoing study that aims to determine the feasibility of capturing sensor-based data at home and to compare the sensor-based outcomes with conventional outcomes. We describe the methodology used in the assessment protocol and present preliminary results of feasibility measures and examples of data related to medication-taking behavior, activity levels, and sleep.

METHODS: The EVALUATE-AD (Ecologically Valid, Ambient, Longitudinal and Unbiased Assessment of Treatment Efficacy in Alzheimer's Disease) trial is a longitudinal naturalistic observational cohort study recruiting 30 patients and 30 spouse coresident care partners. Participants are monitored continuously using a home-based sensing and computing system for up to 24 months. Outcome measures of the automated system are compared with conventional clinical outcome measures in AD. Acceptance of the home system and protocol are assessed by rates of dropout and protocol adherence. After completion of the study monitoring period, a composite model using multiple functional outcome measures will be created that represents a behavioral-activity signature of initiating or discontinuing AD-related medications, such as cholinesterase inhibitors, memantine, or antidepressants.

RESULTS: The home-based sensing and computing system has been well accepted by individuals with cognitive impairment and their care partners. Participants showed good adherence to the completion of a weekly web-based health survey. Daily activity, medication adherence, and total time in bed could be derived from algorithms using data from the sensing and computing system. The mean monitoring time for current participants was 14.6 months. Medication adherence, as measured with an electronic pillbox, was 77% for participants taking AD-related medications.

CONCLUSIONS: Continuous, home-based assessment provides a novel approach to test the impact of new or existing dementia treatments generating objective, clinically meaningful measures related to cognition and everyday functioning. Combining this approach with the current clinical trial methodology may ultimately reduce trial durations, sample size needs, and reliance on a clinic-based assessment.

DERR1-10.2196/17603.

RevDate: 2020-06-09

Yin J, Reiman EM, Beach TG, et al (2020)

Effect of ApoE isoforms on mitochondria in Alzheimer disease.

Neurology, 94(23):e2404-e2411.

OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.

METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).

RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.

CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.

RevDate: 2020-06-19

Obrenovich M, Jaworski H, Tadimalla T, et al (2020)

The Role of the Microbiota-Gut-Brain Axis and Antibiotics in ALS and Neurodegenerative Diseases.

Microorganisms, 8(5):.

: The human gut hosts a wide and diverse ecosystem of microorganisms termed the microbiota, which line the walls of the digestive tract and colon where they co-metabolize digestible and indigestible food to contribute a plethora of biochemical compounds with diverse biological functions. The influence gut microbes have on neurological processes is largely yet unexplored. However, recent data regarding the so-called leaky gut, leaky brain syndrome suggests a potential link between the gut microbiota, inflammation and host co-metabolism that may affect neuropathology both locally and distally from sites where microorganisms are found. The focus of this manuscript is to draw connection between the microbiota-gut-brain (MGB) axis, antibiotics and the use of "BUGS AS DRUGS" for neurodegenerative diseases, their treatment, diagnoses and management and to compare the effect of current and past pharmaceuticals and antibiotics for alternative mechanisms of action for brain and neuronal disorders, such as Alzheimer disease (AD), Amyotrophic Lateral Sclerosis (ALS), mood disorders, schizophrenia, autism spectrum disorders and others. It is a paradigm shift to suggest these diseases can be largely affected by unknown aspects of the microbiota. Therefore, a future exists for applying microbial, chemobiotic and chemotherapeutic approaches to enhance translational and personalized medical outcomes. Microbial modifying applications, such as CRISPR technology and recombinant DNA technology, among others, echo a theme in shifting paradigms, which involve the gut microbiota (GM) and mycobiota and will lead to potential gut-driven treatments for refractory neurologic diseases.

RevDate: 2020-05-22

Nowrangi MA (2020)

Neuropsychiatric Aspects of Alzheimer Dementia: From Mechanism to Treatment.

The Psychiatric clinics of North America, 43(2):383-397.

Developing disease-modifying treatments for Alzheimer dementia requires innovative approaches to identify novel biological targets during the course of the disease. Treatment development for the neuropsychiatric symptoms of Alzheimer may benefit from a mechanistic approach to treatment. There has been progress in identifying mild forms of behavioral impairment along the Alzheimer spectrum that may lead to additional insights into progression to dementia as well as the fundamental mechanisms of the symptoms. Developing therapies for complex neurobehavioral syndromes may require the translation of mechanistic insights into therapy, which may both improve the symptoms and delay progression to dementia in certain patients.

RevDate: 2020-06-22

Vicario A, GH Cerezo (2020)

[The cognitive-behavioural impact of hypertension].

Hipertension y riesgo vascular, 37(3):125-132.

Arterial hypertension is considered the main modifiable vascular risk factor that causes silent damage to brain vessels. This vascular brain injury could be the common nucleus that justifies the cognitive (cognitive impairment, dementia and Alzheimer's disease) and behavioural symptoms (late-life depression) of target organ damage mediated-hypertension. Incomplete knowledge about the complex pathophysiology that links hypertension with cognitive-behavioural changes is overlooking brain involvement and underestimating cardio and cerebrovascular risk. The confluence of cognitive impairment, depression and arterial hypertension in elderly adults, warns of the need for a comprehensive evaluation to plan treatment, improve prognosis and contribute to reducing the risk of dementia and its incidence.

RevDate: 2020-06-23

Peters C, Bascuñán D, Burgos CF, et al (2020)

Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease.

Neurobiology of disease, 141:104938.

INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease.

METHODS: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties.

RESULTS: In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays.

DISCUSSION: Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy.

SIGNIFICANCE: Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool.

RevDate: 2020-06-26

Muñoz P, Ardiles ÁO, Pérez-Espinosa B, et al (2020)

Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease.

Mechanisms of ageing and development, 189:111250 pii:S0047-6374(20)30046-4 [Epub ahead of print].

Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.

RevDate: 2020-05-18

Puente-Castro A, Fernandez-Blanco E, Pazos A, et al (2020)

Automatic assessment of Alzheimer's disease diagnosis based on deep learning techniques.

Computers in biology and medicine, 120:103764.

Early detection is crucial to prevent the progression of Alzheimer's disease (AD). Thus, specialists can begin preventive treatment as soon as possible. They demand fast and precise assessment in the diagnosis of AD in the earliest and hardest to detect stages. The main objective of this work is to develop a system that automatically detects the presence of the disease in sagittal magnetic resonance images (MRI), which are not generally used. Sagittal MRIs from ADNI and OASIS data sets were employed. Experiments were conducted using Transfer Learning (TL) techniques in order to achieve more accurate results. There are two main conclusions to be drawn from this work: first, the damages related to AD and its stages can be distinguished in sagittal MRI and, second, the results obtained using DL models with sagittal MRIs are similar to the state-of-the-art, which uses the horizontal-plane MRI. Although sagittal-plane MRIs are not commonly used, this work proved that they were, at least, as effective as MRI from other planes at identifying AD in early stages. This could pave the way for further research. Finally, one should bear in mind that in certain fields, obtaining the examples for a data set can be very expensive. This study proved that DL models could be built in these fields, whereas TL is an essential tool for completing the task with fewer examples.

RevDate: 2020-05-22

Yu X, Li Y, X Mu (2020)

Effect of Quercetin on PC12 Alzheimer's Disease Cell Model Induced by Aβ25-35 and Its Mechanism Based on Sirtuin1/Nrf2/HO-1 Pathway.

BioMed research international, 2020:8210578.

Objective: This study is aimed at studying the effect of quercetin on the Alzheimer disease cell model induced by Aβ25-35 in PC12 cells and its mechanism of action.

Methods: The AD cell model was established by Aβ25-35. Quercetin was used at different concentrations (0, 10, 20, 40, and 80 μmol/L). The morphology of cells was observed, and the effect on cell survival rate was detected by the MTT method. Cell proliferation was detected by the SRB method. The contents of LDH, SOD, MDA, GSH-Px, AChE, CAT, and T-AOC were detected by kits. The expression of sirtuin1/Nrf2/HO-1 was detected by RT-qPCR and Western blot.

Results: PC12 cells in the control group grew quickly and adhered well to the wall, most of which had extended long axons and easily grew into clusters. In the model group, cells were significantly damaged and the number of cells was significantly reduced. It was found that PC12 cells were swollen, rounded, protruding, and retracting, with reduced adherent function and floating phenomenon. Quercetin could increase the survival rate and proliferation rate of PC12 cells; reduce the levels of LDH, AChE, MDA, and HO-1 protein; and increase the levels of SOD, GSH-Px, CAT, T-AOC, sirtuin1, and Nrf2 protein.

Conclusion: Quercetin can increase the survival rate of PC12 injured by Aβ25-35, promote cell proliferation, and antagonize the toxicity of Aβ; it also has certain neuroprotective effects. Therefore, quercetin is expected to become a drug for the treatment of AD.

RevDate: 2020-06-12

Nasseri B, Zareian P, H Alizade (2020)

Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway.

International immunopharmacology, 84:106546.

Apelin is a neuropeptide that plays an important role in neuronal protection. In this study, we investigated the effects of apelin intracerebroventricular administration on spatial learning and memory-related behaviors, and necroptosis signaling pathways in the hippocampus of streptozotocin (STZ) -injected rats. Apelin treatment was implemented following STZ-induced dementia for 15 days. After conducting a behavioral test (Morris Water Maze), the cellular and molecular aspects were examined to detect the apelin effect on the necroptosis signaling pathway. We demonstrated that STZ administration significantly slowed down the learning capability. However apelin treatment notably reversed this neuroinflammation induced behavioral impairment. Furthermore, molecular investigations showed that apelin treatment reduced the hippocampal RIP1, RIP3, and TNF-α level. Our results suggest that apelin treatment attenuates STZ-induced dementia. This effect may be mediated by inhibition of the necroptosis signaling pathway which seems to be associated with the ability of apelin to reduce central TNF-α level. This data provides evidence of the neuroprotective effect of apelin on STZ-induced learning and memory impairment and characterize some of the underlying mechanisms.

RevDate: 2020-05-15

Volicer L (2020)

Importance of Distinguishing Reactive and Proactive Aggression in Dementia Care.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

Aggressive behavior is one of the most disturbing symptoms of Alzheimer disease and other progressive neurodegenerative dementias. Development of strategies for management of aggressive behaviors in people with dementia is hindered by a lack of recognition that aggression is not a uniform behavioral construct. It is possible to distinguish 2 types of aggression: reactive or impulsive aggression and proactive or premeditated aggression. Research concerning aggressive behaviors in people with dementia is hindered by scales describing behavioral symptoms of dementia which do not distinguish between reactive and proactive aggressions because they do not consider the factors leading to these behaviors. Reactive aggression is caused by lack of understanding, leading to rejection of care, while proactive aggression could be caused by a psychopathic personality, hallucinations or delusions, and other determinants. It is difficult to underestimate the importance of distinguishing reactive and proactive aggressions in people with dementia because there are different strategies that can be used for management of these behaviors. For reactive aggression, delayed treatment, distraction, improved communication, and change in treatment strategy is useful, while antipsychotic medication may be needed for treatment of proactive aggression. Dementia is increasing the risk of both types of aggressions and antidepressant treatment can be helpful. Most importantly, persons exhibiting reactive aggression should not be labeled "aggressors" because this behavior could be caused by unmet persons' needs, pain and poor communication with care providers.

RevDate: 2020-06-13

Turkez H, Cacciatore I, Arslan ME, et al (2020)

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Biomolecules, 10(5):.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aβ1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aβ1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aβ1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

RevDate: 2020-05-11

Kurth S, Wojtasik V, Lekeu F, et al (2020)

Efficacy of Cognitive Rehabilitation Versus Usual Treatment at Home in Patients With Early Stages of Alzheimer Disease.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

INTRODUCTION: Assessing the benefit of cognitive rehabilitation (CR) remains difficult.

METHOD: An observational study was conducted in 33 patients with early-stage Alzheimer disease and their caregiver included in a clinical CR program at home, compared to 17 patients who received usual treatment. Evaluation of patient's dependence and objective and subjective caregiver's burden was performed by the caregiver with a research tool focusing on impairment in daily activities related to cognitive deficits.

RESULTS: Repeated measures analysis of variance showed a time by group interaction (P < .05), with decreased patient's dependence for adapted activities at 1 year in the CR group. Lawton scale for daily activities showed also a time by group interaction (P < .05), with increased dependence at 1 year in the control group. There was a significant decrease in Mini-Mental State Examination scores in both groups at 1-year follow-up (P < .05). Concerning caregiver's subjective burden, there was a trend for the time by group interaction (P = .07), and post hoc Tukey test showed that subjective burden was decreased in the CR group (P < .05). This was confirmed by nonparametric Mann-Whitney analysis on differences between follow-up and baseline evaluation (P < .05).

CONCLUSION: This observational study in a clinical setting is in line with the benefit of CR reported in recent randomized controlled trials. The benefit obtained for adapted daily activities remained after 1 year, even if global cognition declined. Moreover, caregiver's subjective burden related to all relevant daily activities evaluated within the CR program was decreased after 1 year in our clinical setting.

RevDate: 2020-05-22

Doulah A, Mahmoodi G, M Pourmahdi Borujeni (2020)

Evaluation of the pre-treatment effect of Centella asiatica medicinal plants on long-term potentiation (LTP) in rat model of Alzheimer's disease.

Neuroscience letters, 729:135026.

The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer's disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats' brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.

RevDate: 2020-06-19

Cabinio M, Rossetto F, Isernia S, et al (2020)

The Use of a Virtual Reality Platform for the Assessment of the Memory Decline and the Hippocampal Neural Injury in Subjects with Mild Cognitive Impairment: The Validity of Smart Aging Serious Game (SASG).

Journal of clinical medicine, 9(5):.

Due to the lack of pharmacological treatment for dementia, timely detection of subjects at risk can be of seminal importance for preemptive rehabilitation interventions. The aim of the study was to determine the usability of the smart aging serious game (SASG), a virtual reality platform, in assessing the cognitive profile of an amnestic mild cognitive impairment (aMCI) population, its validity in discriminating aMCI from healthy controls (HC), and in detecting hippocampal degeneration, a biomarker of clinical progression towards dementia. Thirty-six aMCI and 107 HC subjects were recruited and administered the SASG together with a neuropsychological evaluation. All aMCI and 30 HC subjects performed also an MRI for hippocampal volume measurement. Results showed good usability of the SASG despite the low familiarity with technology in both groups. ROC curve analyses showed similar discriminating abilities for SASG and gold standard tests, and a greater discrimination ability compared to non-specific neuropsychological tests. Finally, linear regression analysis revealed that the SASG outperformed the Montreal cognitive assessment test (MoCA) in the ability to detect neuronal degeneration in the hippocampus on the right side. These data show that SASG is an ecological task, that can be considered a digital biomarker providing objective and clinically meaningful data about the cognitive profile of aMCI subjects.

RevDate: 2020-05-08

Attia H, Albuhayri S, Alaraidh S, et al (2020)

Biotin, coenzyme Q10, and their combination ameliorate aluminium chloride-induced Alzheimer's disease via attenuating neuroinflammation and improving brain insulin signaling.

Journal of biochemical and molecular toxicology [Epub ahead of print].

Insulin is important for brain function and neuronal survival. Insulin signaling is initiated by the phosphorylation of insulin receptor substrate-1 (IRS-1) at tyrosine (pTyr) residue. However, IRS-1 is inhibited by phosphorylation at serine (pSer). In Alzheimer's disease (AD), oxidative stress and accumulation of amyloid beta (Aβ) induce neuroinflammation, which augments pSer-IRS-1 and reduces pTyr-IRS-1 disturbing insulin signaling pathway. Coenzyme Q10 (CoQ10) and biotin possess antioxidant and anti-inflammatory properties, and, in this study, their impact on insulin signaling is investigated in an aluminium chloride (AlCl3) model of AD. AD was induced by oral administration of AlCl3 (75 mg/kg) for 60 days. Biotin (2 mg/kg), CoQ10 (10 mg/kg), and their combination were supplemented concomitantly with AlCl3 for 60 days. Memory test and histological examination were performed. Brain levels of lipid peroxides, antioxidants (reduced glutathione and superoxide dismutase), inflammatory markers (tumor necrosis factor-α, interleukin-6 [IL-6], IL-1, and nuclear factor κB), and phosphorylated Akt (survival kinase) as well as protein levels of Aβ, IRS-1 (pTyr and pSer), and caspase-3 (apoptotic marker) were determined. AlCl3 resulted in impaired memory, significant increase in Aβ, lipid peroxides, inflammatory markers, caspase-3, and pSer-IRS-1, with significant reduction of the antioxidants, pTyr-IRS-1, and p-Akt reflecting Aβ-induced inflammation and defective insulin signaling. Histological examination revealed focal aggregations of inflammatory cells and neuronal degeneration. The biochemical deviations and histological changes were attenuated by the concomitant treatment with biotin and, to greater extent, with CoQ10 and the combination. In conclusion, biotin and CoQ10 could protect against AD via attenuating inflammatory response and enhancing insulin signaling.

RevDate: 2020-06-11

Maron R, Armony G, Tsoory M, et al (2020)

Peptide Interference with APP and Tau Association: Relevance to Alzheimer's Disease Amelioration.

International journal of molecular sciences, 21(9):.

The two major proteins involved in Alzheimer's disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390-412), APP2 (713-730), Tau1 (19-34) and Tau2 (331-348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model-APP double transgenic (Tg) 5xFAD-as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1-42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function.

RevDate: 2020-06-17

Pérez-González M, Mendioroz M, Badesso S, et al (2020)

PLA2G4E, a candidate gene for resilience in Alzheimer´s disease and a new target for dementia treatment.

Progress in neurobiology, 191:101818.

Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.

RevDate: 2020-05-21
CmpDate: 2020-05-21

Kadah A, Khoury T, W Sbeit (2020)

Early Buried Bumper Syndrome Treated by Bedside Replacement.

The Israel Medical Association journal : IMAJ, 22(5):315-319.

BACKGROUND: Buried bumper syndrome (BBS) mostly occurs as a late complication after percutaneous endoscopic gastrostomy (PEG) insertion; however, early BBS has been rarely reported, and the treatment of this condition is still unclear.

OBJECTIVES: To evaluate the Seldinger technique for treatment of early BBS after PEG insertion.

METHODS: We report two cases of early BBS in two consecutive patients who underwent PEG insertion to maintain oral intake. The first patient was an 83-year-old woman showing Alzheimer type dementia, while the other one was a 76-year-old man who presented with maxillary cancer and treated with radiotherapy followed by left maxillectomy. Post-surgery, he developed progressive difficulty of swallowing due to mouth deformation and treatment related nerve toxicity. The first patient presented with fever and purulent discharge from the gastrostomy insertion site, without ability to rotate or slide the tube through the stoma 10 days after the PEG insertion. The man was admitted to the hospital 5 days following PEG insertion due to a fever of 38°C and peritubal swelling with purulent discharge. In addition, the tube could not rotate or slide through the stoma.

RESULTS: Buried bumper syndrome was demonstrated by computed tomography scan. Gastroscopy and gastrostomy tube replacement was performed successfully according to the Seldinger technique (replacement over guidewire) in both cases. Correct intragastric tube positioning was demonstrated radiographically before resuming tube feeding. The two patients were discharged in good physical condition several days later.

CONCLUSIONS: External replacement over guide wire should be considered in such cases.

RevDate: 2020-05-09

Solár P, Zamani A, Kubíčková L, et al (2020)

Choroid plexus and the blood-cerebrospinal fluid barrier in disease.

Fluids and barriers of the CNS, 17(1):35.

The choroid plexus (CP) forming the blood-cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.

RevDate: 2020-05-06

Expert Panel on Neurological Imaging, Moonis G, Subramaniam RM, et al (2020)

ACR Appropriateness Criteria® Dementia.

Journal of the American College of Radiology : JACR, 17(5S):S100-S112.

Degenerative disease of the central nervous system is a growing public health concern. The primary role of neuroimaging in the workup of patients with probable or possible Alzheimer disease has typically been to exclude other significant intracranial abnormalities. In general, the imaging findings in structural studies, such as MRI, are nonspecific and have limited potential in differentiating different types of dementia. Advanced imaging methods are not routinely used in community or general practices for the diagnosis or differentiation of forms of dementia. Nonetheless, in patients who have been evaluated by a dementia expert, FDG-PET helps to distinguish Alzheimer disease from frontotemporal dementia. In patients with suspected dementia with Lewy bodies, functional imaging of the dopamine transporter (ioflupane) using SPECT may be helpful. In patients with suspected normal-pressure hydrocephalus, DTPA cisternography and HMPAO SPECT/CT brain may provide assessment. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

RevDate: 2020-06-23

Hershenhouse KS, Shauly O, Gould DJ, et al (2019)

Meningeal Lymphatics: A Review and Future Directions From a Clinical Perspective.

Neuroscience insights, 14:1179069519889027.

The recent discovery of lymphatic vessels in the meningeal layers calls into question the known mechanisms of fluid and macromolecule homeostasis and immunoregulation within the central nervous system. These meningeal lymphatic vessels and their potential role in the pathophysiology of neurological disease have become a rapidly expanding area of research, with the hopes that they may provide a novel therapeutic target in the treatment of many devastating conditions. This article reviews the current state of knowledge surrounding the anatomical structure of the vessels, their functions in fluid and solute transport and immune surveillance, as well as their studied developmental biology, relationship with the novel hypothesized "glymphatic" system, and implications in neurodegenerative disease in animal models. Furthermore, this review summarizes findings from the human studies conducted thus far regarding the presence, anatomy, and drainage patterns of meningeal lymphatic vessels and discusses, from a clinical perspective, advancements in both imaging technologies and interventional methodologies used to access ultrafine peripheral lymphatic vessels.

RevDate: 2020-05-14

Royea J, Lacalle-Aurioles M, Trigiani LJ, et al (2020)

AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease.

Hypertension (Dallas, Tex. : 1979), 75(6):1464-1474.

Antihypertensive medications targeting the renin-angiotensin system have lowered the incidence and progression of Alzheimer disease. Understanding how these medications function could lead to novel therapeutic strategies. AT4Rs (angiotensin IV receptors) have been associated with angiotensin receptor blockers' cognitive, cerebrovascular, and neuroinflammatory rescue in Alzheimer disease models. Yet, whether AT4Rs act alone or with AT2Rs remains unknown. Here, we investigated whether AT2Rs contribute to losartan's benefits and whether chronic AT2R activation could mimic angiotensin receptor blocker benefits in transgenic mice overexpressing familial Alzheimer disease mutations of the human APP (amyloid precursor protein). Losartan-treated mice (10 mg/kg per day, drinking water, 7 months) received intracerebroventricular (1 month) administration of vehicle or AT2R antagonist PD123319 (1.6 nmol/day). PD123319 countered losartan's benefits on spatial learning and memory, neurovascular coupling, and hampered those on oxidative stress and nitric oxide bioavailability. PD123319 did not oppose losartan's benefits on short-term memory and vasodilatory function and had no benefit on neuroinflammation or Aβ (amyloid β) pathology. Mice receiving either vehicle or selective AT2R agonist compound 21 (intracerebroventricular: 1 nmol/day, 1 month or drinking water: 10 mg/kg per day, 7 months), showed no improvement in memory, vasodilatory function, or nitric oxide bioavailability. Compound 21 treatment normalized neurovascular coupling, reduced astrogliosis independent of persisting microgliosis, and exacerbated oxidative stress in APP mice. Compound 21 reduced dense core Aβ plaques, but not diffuse plaques or Aβ species. Our findings suggest that targeting AT2Rs is not an ideal strategy for restoring Aβ-related cognitive and cerebrovascular deficits.

RevDate: 2020-05-03

Frydrýšková K, Mašek T, M Pospíšek (2020)

Changing faces of stress: Impact of heat and arsenite treatment on the composition of stress granules.

Wiley interdisciplinary reviews. RNA [Epub ahead of print].

Stress granules (SGs), hallmarks of the cellular adaptation to stress, promote survival, conserve cellular energy, and are fully dissolved upon the cessation of stress treatment. Different stresses can initiate the assembly of SGs, but arsenite and heat are the best studied of these stresses. The composition of SGs and posttranslational modifications of SG proteins differ depending on the type and severity of the stress insult, methodology used, cell line, and presence of overexpressed and tagged proteins. A group of 18 proteins showing differential localization to SGs in heat- and arsenite-stressed mammalian cell lines is described. Upon severe and prolonged stress, physiological SGs transform into more solid protein aggregates that are no longer reversible and do not contain mRNA. Similar pathological inclusions are hallmarks of neurodegenerative diseases. SGs induced by heat stress are less dynamic than SGs induced by arsenite and contain a set of unique proteins and linkage-specific polyubiquitinated proteins. The same types of ubiquitin linkages have been found to contribute to the development of neurodegenerative disorders such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). We propose heat stress-induced SGs as a possible model of an intermediate stage along the transition from dynamic, fully reversible arsenite stress-induced SGs toward aberrant SGs, the hallmark of neurodegenerative diseases. Stress- and methodology-specific differences in the compositions of SGs and the transition of SGs to aberrant protein aggregates are discussed. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.

RevDate: 2020-05-03

Kang J, Shin DW, Han K, et al (2020)

Risk of dementia in prostate cancer survivors: A nationwide cohort study in Korea.

Current problems in cancer pii:S0147-0272(20)30061-1 [Epub ahead of print].

OBJECTIVES: To investigate the effects of prostate cancer (PC) and various treatment modalities for PC, specifically androgen deprivation therapy (ADT), on the risk of dementia and dementia subtypes in PC survivors.

MATERIAL AND METHODS: A total of 51,252 patients newly diagnosed with PC from 2007 to 2013, who had no prior diagnosis of cancer or dementia, were included and matched with 209,659 non-cancer control. The screening subset was comprised of subjects who participated in a health screening program. We used Cox proportional hazards model to estimate the relative risk of dementia and dementia subtypes according to the primary treatment for the PC.

RESULTS: Compared to non-PC matched controls, PC survivors showed slightly higher risk for dementia and Alzheimer disease (AD) only in the screening cohort. While PC survivors who underwent ADT were higher risk for dementia and AD, patients who underwent surgery were lower risk for dementia and AD, compared to the non-cancer population. Compared to surgery, ADT, surgery + ADT, and active surveillance/watchful waiting showed a significantly elevated risk for dementia.

CONCLUSION: PC survivors had slightly higher risk for dementia compared to non-PC controls, which might be related to the screening effects of PC. The risk for dementia was most prominent among PC patients who underwent ADT, followed by patients who underwent AS/WW, and those who underwent surgery + ADT. This finding suggests that individualized ADT strategies that consider the survival benefit and underlying dementia risk in PC survivors are necessary.

RevDate: 2020-05-10

Hrabinova M, Pejchal J, Kucera T, et al (2020)

Is It the Twilight of BACE1 Inhibitors?.

Current neuropharmacology pii:CN-EPUB-106293 [Epub ahead of print].

β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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